We have continued to study the immunopathogenic role of dendritic cells in human immunodeficiency virus (HIV) infection and disease progression. The different populations of cells with dendritic morphology present in peripheral blood continue to be studied. This analysis has been extended to the observation that monocytes, when treated with GM-CSF and interleukin (IL)-4, develop a dendritic morphology. This population actually contains two distinct populations, one that expresses CD83, a marker of blood and lymphoid dendritic cells, and a second that expresses CD1a, a marker of Langerhans cells. A model has been developed that simulates the cellular interactions that occur in the microenvironment of lymphoid organs. This model is more physiologic than previous in vitro models in that the majority of viral replication occurs in the paracortical regions of the lymph node in activated, acutely infected CD4 positive T cells. Using this model, multiple activities produced by CD8 positive T cells have been identified. One is non-specific in that is found in CD8 positive T cells from uninfected individuals, while the other activity has only been identified in HIV-infected individuals and unlike the non-specific factor is gamma irradiation sensitive. It is likely that DC, as the most potent antigen presenting cell for primary immune responses, are involved in both the initiation and propagation of HIV disease. Epidemiological evidence from Africa suggests the HIV- disease has a more rapid course and a more efficient transmission compared to the United States which has been suggested to be due to immune activation. We have studied the effect of prior activation of T cells on the ability of DC to induce infection in CD4 positive T cells. Two weeks after tetanus immunization, DC can induce a more productive infection in CD4 positive T cells with 25 to 100 times less input virus. Thus, this enhancement of overall viral replication and ability to initiate an infection with much less virus during immune system activation demonstrates the peril of having an activated immune system upon exposure to HIV.